More individuals are becoming overweight and obese, a condition now considered to be the most common nutritional disorder in the industrialized world today. Overweight and obesity can be defined by a body-mass index exceeding 25 or 30. Normal values range from 18 to 25. In the US 34% of the population is overweight and another 27% is obese. This means that more than 60% of the entire population in the US has what can be defined as having a weight problem, which is likely to cause severe health problems, such as hypertension and elevated blood lipids, all risk factors for cardiovascular disease.
Overweight and obesity are caused by an imbalance between energy intake and energy use. In the industrialized world we tend to eat too much and engage in physical activities too little. However, the likelihood of becoming fat under these conditions is not the same for everyone, as witnessed by the fact that slim individuals exist under the same conditions as those who are overweight. Furthermore, the revelation that nutritional factors may control gene expression has opened up the possibility of developing novel therapeutic alternatives to treat obesity. The major problem in therapeutic strategies aimed to treat obesity and decrease body fat deposit is that such strategies act against potent and multiple mechanisms evolved in order to store metabolic energy and support survival under the periods when nutrition is scarce.
Once stored in adipose tissue, the metabolic energy is only released under the conditions of high food intake negative energy balance, namely during fasting and/or physical exercise. Importantly, the loss of the energy content of the tissue under these conditions results from both, increased secretion of fatty acids from adipose tissue cells, and catabolism of tissue lipids, which increases during fasting (Wang T et al., Obesity Research 11:880-887, 2003).
Fats are composed of fatty acids and fat is the most calorie dense nutrient. High fat diets are linked to excess weight gain, but not all fats are equal. In the gastrointestinal tract fats are broken down into fatty acids by lipases and absorbed into the intestinal cells. In intestinal cells, the lymphatic system and the liver, fatty complexes are produced to transport fatty acids. In the circulation these fatty acids are released by lipases entering cells or getting integrated into the cell membranes. Most fatty acids are used for energy, but some, especially polyunsaturated fatty acids have other functions including interacting with cellular proteins, which in turn enter the nucleus and turn genes off and on. These genes are known to encode proteins important in controlling energy production from glucose and fat.
Fatty acids differ in their three-dimensional structure, which is determined by the chain-length of the molecule and the number of double bonds present. The most common dietary fats are medium to long chains fatty acids. Saturated fatty acids have no double bonds, resulting in a straight molecule. If a double bond is present then an angle of 120 degrees is produced. Thus, polyunsaturated fatty acids (PUFA's) have a completely different spatial resolution when compared to the saturated fatty acids. The differences in three dimensional structure between fatty acids means that while the PUFA's can act as signalling agents to the cell, switching gene transcription off or on, the saturated fatty acids are not recognised and have no effect. In the laboratory calorimeter all fats irrespective of their saturated or unsaturated nature generate 9 kcal of energy per gram, but when part of the diet, PUFA's give completely different net effects on metabolic energy production and weight gain compared to the saturated fatty acids. Thus, saturated fatty acids are the main source of energy in the human body, while PUFAs fulfil a different function. PUFA's are derived mainly from seeds, nuts or fish oil. They may have their first double bond located either three, six or nine carbon atoms away from the chain end. Thus, they are known either as omega-3, omega-6 and omega-9 fatty acids, or n-3, n-6 and n-9 fatty acids. Humans can not synthesise fatty acids with double bonds at the 3 or 6 location making these fatty acids essential dietary components. In certain cases both types of PUFA's may have the same action. One example is the effects of PUFA's on suppressing lipid synthesis in the liver while at the same time up-regulating fatty acid oxidation in the liver and skeletal muscle. It has also been demonstrated that PUFA's decrease the transcription of hepatic genes encoding glycolytic and lipogenic enzymes. The effect of the PUFA's on gene expression in the liver and muscle thus leads to increased metabolism and decreased fat storage, helping to prevent weight gain. Energy conversion is mainly located to the mitochondria within the cell. The mitochondria preferentially oxidise medium- and short-chain fatty acids. Energy released is converted into ATP, which is used for a large number of energy dependent processes. However, mitochondrial energy conversion is not 100% efficient, and part of the metabolic energy is released as heat. The efficiency of mitochondrial energy conversion is modulated by mitochondrial uncoupling proteins. Further, the PUFA's also affect another site for metabolic energy conversion, namely the peroxisome also located inside the cell membrane. While the main role of mitochondria is the production of the energy-rich ATP, peroxisomes are more active in the generation of heat, while shortening polyunsaturated long-chain fatty acids before their further oxidation in mitochondria. The net effect is increased production of heat instead of increasing the fat deposits. PUFA's are peroxisome proliferators increasing the amount and the activity of peroxisomes.
Moreover, during fasting, a major physiological situation leading to the depression of adiposity, energy content of fat cells may be reduced by several mechanisms, like upregulation of mitochondrial uncoupling protein 2, see (Millet L et al. J. Clin. Invest. 100:2665-2670, 1997; Vidal-Puig A. et al. Obesity Research 7:133-140, 1999). Moreover, it has been shown that reduction of abdominal fat by dietary omega-3 PUFAs in rats is associated with increased levels of expression of uncoupling proteins 2 and 3 in adipose tissue (Oudart H. et al. Int. J. Obesity and Metab. Disord. 24 Supp 1:S130, 2000; Hun C. S. et al. Biochem. Biophys. Res. Commun. 259:85-90, 1999) Furthermore, it has also been shown that a 6 g/day substitution of visible fat by fish oil in healthy adults reduces fat mass and increases basal lipid oxidation (Couet C, Delarue J, Ritz P, Antoine J-M and Lamisse F, 1997, International Journal of Obesity 21: 637-643), but at the same time the fish oil had no significant effect on body weight reduction. Finally, US 2003203004 A1 descibes a composition comprising short and long chain fatty acids which are useful for the management of body weight.